The Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The article by Aharon-Peretz et al. (Nov. 4 issue)1 is of considerable interest to us because it substantiates our previously published study2 in which glucocerebrosidase mutations were identified in brain samples from patients with parkinsonism. Autopsy samples from 57 patients with pathologically confirmed Parkinson's disease and 44 controls were screened by sequencing the entire glucocerebrosidase gene. Eight samples from the patients (14 percent) had glucocerebrosidase mutations, as compared with none of the samples from the control group. In addition, we recently sequenced 26 brain samples (from the U.K. Parkinson's Disease Society Tissue Bank at Imperial College, London) from patients in whom Parkinson's disease had been diagnosed between the ages of 42 and 78 years and found 2 (8 percent) that carried glucocerebrosidase mutations (D140H in 1 and RecNciI in the other).3 These findings, based on definitive diagnoses at autopsy, suggest that heterozygosity for mutations in the glucocerebrosidase gene may be a risk factor for parkinsonism among groups other than Ashkenazim. Since 4 of our 10 positive samples had mutations other than N370S and L444P, gene sequencing appears to be required to determine the true frequency of this association.
Michael J. Eblan, B.A.
Jamie M. Walker, B.A.
Ellen Sidransky, M.D.
National Institutes of Health
Bethesda, MD 20892-3708
sidranse@irp.nimh.nih.gov
References
Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2004;351:1972-1977.
Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 2004;81:70-73.
Tayebi N, Stubblefield BK, Park JK, et al. Reciprocal and nonreciprocal recombination at the glucocerebrosidase gene region: implications for complexity in Gaucher disease. Am J Hum Genet 2003;72:519-534.
To the Editor: Aharon-Peretz et al. report that of 99 Ashkenazi Jewish patients with Parkinson's disease, 31 percent were carriers of Gaucher's disease. We (who previously reported the occurrence of severe, early-onset, drug-resistant parkinsonism in non-neuronopathic Gaucher's disease1) and others using the same paradigm found lower, statistically nonsignificant rates.2,3 Among 150 patients with Parkinson's disease in five Israeli centers, including Aharon-Peretz and colleagues' center, and among 160 American Ashkenazi Jewish patients with Parkinson's disease, 10.6 percent and 10.7 percent, respectively, were carriers of Gaucher's disease; among autopsy samples from persons with sporadic Parkinson's disease, 14 percent had Gaucher mutations.4 The interpretation that there is a significant incidence of early-onset parkinsonism among hundreds of thousands of carriers of Gaucher's disease could result in the instigation of large-scale screening policies among Ashkenazi Jews and potentially lead to recommendations for enzyme replacement or substrate-reduction therapy merely for the hypothetical prevention of neurologic disease. Both situations have enormous implications on personal and societal levels. Hence, the findings of the current study must be confirmed in larger cohorts before these data can be accepted.
Ari Zimran, M.D.
Orit Neudorfer, M.D.
Deborah Elstein, Ph.D.
Shaare Zedek Medical Center
91031 Jerusalem, Israel
zimran@md.huji.ac.il
References
Neudorfer O, Giladi N, Elstein D, et al. Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM 1996;89:691-694.
Neudorfer O. Occurrence of parkinsonianism among patients and carriers of type I Gaucher disease. (M.D. thesis. Jerusalem, Israel: Hebrew University–Hadassah Medical School, 1994.)
Clark LN, Nicolai A, Afridi S, et al. Pilot association study of the beta-glucocerebrosidase N370S allele and Parkinson's disease in subjects of Jewish ethnicity. Mov Disord 2004;20:100-105.
Sidransky E. Gaucher disease: complexity in a "simple" disorder. Mol Genet Metab 2004;83:6-15.
To the Editor: Aharon-Peretz and colleagues report that mutations in the glucocerebrosidase gene confer increased susceptibility to Parkinson's disease. Glucocerebroside, which comprises the monosaccharide glucose attached to ceramide, represents a key intermediate both in the synthesis of neutral and complex sialylated glycosphingolipids and in their degradation by glucocerebrosidase activity. The published links between glycosphingolipid metabolism and parkinsonism include treatment with GM1, a sialylated, N-acetylgalactosamine–containing glycosphingolipid, in patients who have Parkinson's disease.1
We explored the possibility of an interaction between glucocerebrosides and -synuclein, a seminal protein in the pathogenesis of Parkinson's disease, after our discovery of a unique -synuclein variant in human-brain homogenates that carried sialic acid and N-acetylgalactosamine.2 Using high-performance thin-layer chromatography and nanoelectrospray ionization quadrupole time-of-flight mass spectrometry,3 we unexpectedly observed strong binding of -synuclein to eight human-brain–derived glycosphingolipids that contained glucocerebroside (glucosylceramide) as their core structure (Figure 1). There is evidence that the processing of -synuclein occurs within lysosomes,4 the site of glycosphingolipid metabolism. Our observation of direct binding of -synuclein to glucocerebroside-containing glycosphingolipids provides a possible biochemical link between enzymatic glucocerebrosidase activity and synucleinopathy-associated Parkinson's disease.
Figure 1. Binding of -Synuclein to Glucocerebroside-Containing Glycosphingolipids.
Human-brain–derived gangliosides were separated on high-performance thin-layer chromatography plates that had been precoated with silica gel.3 Panel A shows an overlay assay with wild-type human -synuclein (1 μg per milliliter) probed with a monoclonal IgG1 antibody (sc-12767, Santa Cruz Biotechnology) and developed by alkaline phosphatase activity–linked blue-indigo–like staining (lane 1). Glycosphingolipids were visualized with orcinol (lane 2). Arrows indicate -synuclein–positive sphingolipids awaiting structural confirmation. G denotes gangliosides with one (M), two (D), or three (T) sialic (neuraminic) acid sugars. Panel B lists eight human gangliosides that bound -synuclein (as in Panel A) and that were identified by nanoelectrospray ionization quadrupole time-of-flight mass spectrometry.3 Their shared glucocerebroside (glucosylceramide) core is shown in red. Cer denotes ceramide, Glc glucose, Gal galactose, GalNAc N-acetylgalactosamine, and Neu5Ac N-acetylneuraminic (sialic) acid.
Michael G. Schlossmacher, M.D.
Valerie Cullen, Ph.D.
Harvard Medical School
Boston, MA 02115
mschlossmacher@rics.bwh.harvard.edu
Johannes Müthing, Ph.D.
University of Münster
D-48149 Münster, Germany
References
Schneider JS. GM1 ganglioside in the treatment of Parkinson's disease. Ann N Y Acad Sci 1998;845:363-373.
Shimura H, Schlossmacher MG, Hattori N, et al. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 2001;293:263-269.
Meisen I, Peter-Katalinic J, Müthing J. Direct analysis of silica gel extracts from immunostained glycosphingolipids by nanoelectrospray ionization quadrupole time-of-flight mass spectrometry. Anal Chem 2004;76:2248-2255.
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004;305:1292-1295.
The authors reply: Our study was designed to inquire whether mutations in the glucocerebrosidase gene predispose Ashkenazi Jews to Parkinson's disease. As of February 2002 and for a period of 28 months, 99 Ashkenazi Jews who met research criteria for idiopathic Parkinson's disease were prospectively enrolled, after examination by a single neurologist. We chose to study only patients of Ashkenazi descent because the high rate of carriers of glucocerebrosidase mutations among persons in this ethnic group (1 in 17) would allow us to discern an effect that in other ethnic groups would have been missed. Furthermore, the repertoire of glucocerebrosidase founder mutations causing Gaucher's disease in Ashkenazi Jews is well defined and predominantly limited to the six mutations we studied. In the study by Lwin et al.1 alluded to by Eblan et al., glucocerebrosidase mutations were detected in 8 of 57 brain samples (14 percent) obtained at autopsy from patients with pathologically confirmed Parkinson's disease.
Bearing in mind that no mutations were found in the controls and that the samples were not exclusively from Ashkenazi Jewish patients, we can safely assume that the 31 percent carrier rate among our patients is in line with the 14 percent reported.1 We agree that heterozygosity for mutations in the glucocerebrosidase gene is a risk factor for parkinsonism in groups other than Ashkenazim. Undoubtedly, in such ethnic groups, gene sequencing is required to determine the frequency of glucocerebrosidase mutations.
We are perplexed, however, by the numbers provided by Zimran et al. Among the 150 patients with Parkinson's disease from five Israeli centers, they include our 99 patients, of whom 31 were carriers of Gaucher's disease. We have no details on the remaining 51 patients. Assuming that none were carriers of Gaucher's disease, there still would remain 31 carriers among the 150 patients, which amounts to 20.7 percent. In the American cohort, the incidence of carriers and homozygotes was only 10.7 percent (as compared with 4.3 percent among the controls).2 However, among these 160 Jewish patients, not strictly of Ashkenazi descent, only one mutation (N370S) was studied.
The observations of Schlossmacher et al., linking eight human-brain–derived glycosphingolipids containing glucocerebroside (glucosylceramide) to -synuclein, are exciting. The direct binding of -synuclein to glucocerebroside-containing glycosphingolipids might provide the possible biochemical link between enzymatic glucocerebrosidase activity and Parkinson's disease. Nonetheless, because the relative risk of the development of parkinsonism in a person with a glucocerebroside mutation is unknown, we do not believe that enzyme replacement for hypothetical prevention of a neurologic disease is appropriate.
Ruth Gershoni-Baruch, M.D.
Judith Aharon-Peretz, M.D.
Hanna Rosenbaum, M.D.
Ruth and Bruce Rappaport Faculty of Medicine
31096 Haifa, Israel
rgershoni@rambam.health.gov.il
Michael J. Eblan, B.A.
Jamie M. Walker, B.A.
Ellen Sidransky, M.D.
National Institutes of Health
Bethesda, MD 20892-3708
sidranse@irp.nimh.nih.gov
References
Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2004;351:1972-1977.
Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 2004;81:70-73.
Tayebi N, Stubblefield BK, Park JK, et al. Reciprocal and nonreciprocal recombination at the glucocerebrosidase gene region: implications for complexity in Gaucher disease. Am J Hum Genet 2003;72:519-534.
To the Editor: Aharon-Peretz et al. report that of 99 Ashkenazi Jewish patients with Parkinson's disease, 31 percent were carriers of Gaucher's disease. We (who previously reported the occurrence of severe, early-onset, drug-resistant parkinsonism in non-neuronopathic Gaucher's disease1) and others using the same paradigm found lower, statistically nonsignificant rates.2,3 Among 150 patients with Parkinson's disease in five Israeli centers, including Aharon-Peretz and colleagues' center, and among 160 American Ashkenazi Jewish patients with Parkinson's disease, 10.6 percent and 10.7 percent, respectively, were carriers of Gaucher's disease; among autopsy samples from persons with sporadic Parkinson's disease, 14 percent had Gaucher mutations.4 The interpretation that there is a significant incidence of early-onset parkinsonism among hundreds of thousands of carriers of Gaucher's disease could result in the instigation of large-scale screening policies among Ashkenazi Jews and potentially lead to recommendations for enzyme replacement or substrate-reduction therapy merely for the hypothetical prevention of neurologic disease. Both situations have enormous implications on personal and societal levels. Hence, the findings of the current study must be confirmed in larger cohorts before these data can be accepted.
Ari Zimran, M.D.
Orit Neudorfer, M.D.
Deborah Elstein, Ph.D.
Shaare Zedek Medical Center
91031 Jerusalem, Israel
zimran@md.huji.ac.il
References
Neudorfer O, Giladi N, Elstein D, et al. Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM 1996;89:691-694.
Neudorfer O. Occurrence of parkinsonianism among patients and carriers of type I Gaucher disease. (M.D. thesis. Jerusalem, Israel: Hebrew University–Hadassah Medical School, 1994.)
Clark LN, Nicolai A, Afridi S, et al. Pilot association study of the beta-glucocerebrosidase N370S allele and Parkinson's disease in subjects of Jewish ethnicity. Mov Disord 2004;20:100-105.
Sidransky E. Gaucher disease: complexity in a "simple" disorder. Mol Genet Metab 2004;83:6-15.
To the Editor: Aharon-Peretz and colleagues report that mutations in the glucocerebrosidase gene confer increased susceptibility to Parkinson's disease. Glucocerebroside, which comprises the monosaccharide glucose attached to ceramide, represents a key intermediate both in the synthesis of neutral and complex sialylated glycosphingolipids and in their degradation by glucocerebrosidase activity. The published links between glycosphingolipid metabolism and parkinsonism include treatment with GM1, a sialylated, N-acetylgalactosamine–containing glycosphingolipid, in patients who have Parkinson's disease.1
We explored the possibility of an interaction between glucocerebrosides and -synuclein, a seminal protein in the pathogenesis of Parkinson's disease, after our discovery of a unique -synuclein variant in human-brain homogenates that carried sialic acid and N-acetylgalactosamine.2 Using high-performance thin-layer chromatography and nanoelectrospray ionization quadrupole time-of-flight mass spectrometry,3 we unexpectedly observed strong binding of -synuclein to eight human-brain–derived glycosphingolipids that contained glucocerebroside (glucosylceramide) as their core structure (Figure 1). There is evidence that the processing of -synuclein occurs within lysosomes,4 the site of glycosphingolipid metabolism. Our observation of direct binding of -synuclein to glucocerebroside-containing glycosphingolipids provides a possible biochemical link between enzymatic glucocerebrosidase activity and synucleinopathy-associated Parkinson's disease.
Figure 1. Binding of -Synuclein to Glucocerebroside-Containing Glycosphingolipids.
Human-brain–derived gangliosides were separated on high-performance thin-layer chromatography plates that had been precoated with silica gel.3 Panel A shows an overlay assay with wild-type human -synuclein (1 μg per milliliter) probed with a monoclonal IgG1 antibody (sc-12767, Santa Cruz Biotechnology) and developed by alkaline phosphatase activity–linked blue-indigo–like staining (lane 1). Glycosphingolipids were visualized with orcinol (lane 2). Arrows indicate -synuclein–positive sphingolipids awaiting structural confirmation. G denotes gangliosides with one (M), two (D), or three (T) sialic (neuraminic) acid sugars. Panel B lists eight human gangliosides that bound -synuclein (as in Panel A) and that were identified by nanoelectrospray ionization quadrupole time-of-flight mass spectrometry.3 Their shared glucocerebroside (glucosylceramide) core is shown in red. Cer denotes ceramide, Glc glucose, Gal galactose, GalNAc N-acetylgalactosamine, and Neu5Ac N-acetylneuraminic (sialic) acid.
Michael G. Schlossmacher, M.D.
Valerie Cullen, Ph.D.
Harvard Medical School
Boston, MA 02115
mschlossmacher@rics.bwh.harvard.edu
Johannes Müthing, Ph.D.
University of Münster
D-48149 Münster, Germany
References
Schneider JS. GM1 ganglioside in the treatment of Parkinson's disease. Ann N Y Acad Sci 1998;845:363-373.
Shimura H, Schlossmacher MG, Hattori N, et al. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 2001;293:263-269.
Meisen I, Peter-Katalinic J, Müthing J. Direct analysis of silica gel extracts from immunostained glycosphingolipids by nanoelectrospray ionization quadrupole time-of-flight mass spectrometry. Anal Chem 2004;76:2248-2255.
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004;305:1292-1295.
The authors reply: Our study was designed to inquire whether mutations in the glucocerebrosidase gene predispose Ashkenazi Jews to Parkinson's disease. As of February 2002 and for a period of 28 months, 99 Ashkenazi Jews who met research criteria for idiopathic Parkinson's disease were prospectively enrolled, after examination by a single neurologist. We chose to study only patients of Ashkenazi descent because the high rate of carriers of glucocerebrosidase mutations among persons in this ethnic group (1 in 17) would allow us to discern an effect that in other ethnic groups would have been missed. Furthermore, the repertoire of glucocerebrosidase founder mutations causing Gaucher's disease in Ashkenazi Jews is well defined and predominantly limited to the six mutations we studied. In the study by Lwin et al.1 alluded to by Eblan et al., glucocerebrosidase mutations were detected in 8 of 57 brain samples (14 percent) obtained at autopsy from patients with pathologically confirmed Parkinson's disease.
Bearing in mind that no mutations were found in the controls and that the samples were not exclusively from Ashkenazi Jewish patients, we can safely assume that the 31 percent carrier rate among our patients is in line with the 14 percent reported.1 We agree that heterozygosity for mutations in the glucocerebrosidase gene is a risk factor for parkinsonism in groups other than Ashkenazim. Undoubtedly, in such ethnic groups, gene sequencing is required to determine the frequency of glucocerebrosidase mutations.
We are perplexed, however, by the numbers provided by Zimran et al. Among the 150 patients with Parkinson's disease from five Israeli centers, they include our 99 patients, of whom 31 were carriers of Gaucher's disease. We have no details on the remaining 51 patients. Assuming that none were carriers of Gaucher's disease, there still would remain 31 carriers among the 150 patients, which amounts to 20.7 percent. In the American cohort, the incidence of carriers and homozygotes was only 10.7 percent (as compared with 4.3 percent among the controls).2 However, among these 160 Jewish patients, not strictly of Ashkenazi descent, only one mutation (N370S) was studied.
The observations of Schlossmacher et al., linking eight human-brain–derived glycosphingolipids containing glucocerebroside (glucosylceramide) to -synuclein, are exciting. The direct binding of -synuclein to glucocerebroside-containing glycosphingolipids might provide the possible biochemical link between enzymatic glucocerebrosidase activity and Parkinson's disease. Nonetheless, because the relative risk of the development of parkinsonism in a person with a glucocerebroside mutation is unknown, we do not believe that enzyme replacement for hypothetical prevention of a neurologic disease is appropriate.
Ruth Gershoni-Baruch, M.D.
Judith Aharon-Peretz, M.D.
Hanna Rosenbaum, M.D.
Ruth and Bruce Rappaport Faculty of Medicine
31096 Haifa, Israel
rgershoni@rambam.health.gov.il